Background and purpose: Bruton tyrosine kinase (Btk) is essential for B cell function. Its role in myeloid cells is less understood. Greater insights into Btk significance in myeloid cells are needed to evaluate its potential as a therapeutic target during the effector phase of antibody-induced autoimmune diseases, where inhibiting autoantibody production suppresses tissue inflammation only after a delay. Such a situation can be observed, for example, in acute flares of pemphigoid diseases, a group of autoimmune blistering skin diseases.
Experimental approach: We examined the effect of neutrophil-specific Btk gene deficiency and of the Btk inhibitor ibrutinib on disease in the antibody-transfer model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a model that solely reflects the effector phase. We additionally investigated the effect of Btk inhibitors on responses of neutrophils relevant for autoimmune diseases in vitro.
Key results: Both neutrophil-specific Btk deficiency and ibrutinib administration, systemic or topical, markedly protected against skin inflammation and disrupted established inflammation. Stimulation of murine neutrophils with immune complexes activated Btk and induced the release of leukotriene B4 (LTB4) and reactive oxygen species (ROS). Btk deficiency abolished LTB4 but not ROS release, indicating distinct signalling pathways regulating LTB4 and ROS following Fc? receptor activation.
Conclusions and implications: Our findings demonstrate that EBA skin inflammation is critically controlled by a Fc? receptor-Btk-LTB4 axis in neutrophils. This highlights Btk as promising drug target to treat EBA and potentially other antibody-induced autoimmune diseases.
